Sporadic breast cancer develops through the modification of genes that function to regulate signaling pathways. The consequence of these modifications is to alter the state of signaling pathways in a direction that stimulates tumor development. Signaling pathways that are changed in breast cancer regulate the cell cycle, apoptosis, checkpoint control, and DNA repair. Recently increasing evidence suggests that the aberrant regulation of the PI-3 kinase pathway contributes to the transformation of breast epithelial cells. Germline mutation of the PTEN tumor suppressor, which is a negative regulator of the PI-3 kinase pathway, is associated with a 30-50% risk of developing breast cancer. In sporadic breast cancer, PTEN mutation occurs in approximately 2-5% of cases while reduced PTEN protein expression happens in 33%-48% of cases. These data suggest that alteration of PTEN regulation in the absence of mutation contributes to the development of sporadic breast cancer. We would like to better understand the cause and effect of the dermlgement of the PI-3 kinase pathway in breast tumorigenesis. To study this problem we will develop a model of PTEN inactivation in mouse mammary tissue and compare these tumors to human breast cancer. We will also examine whether the effects of PTEN on gene expression occur solely through regulation of the PI-3 kinase pathway. Finally, we will identify regulators of the PTEN/PI-3 kinase pathway and examine them for alteration in sporadic breast cancer.